Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone) have been employed in human therapy. Almost all therapeutically useful opioids in the benzomorphan and morphinan classes have a phenolic hydroxyl group (OH) at a position which is numbered “8” in the numbering system used for 2,6-methano-3-benzazocines [e.g., cyclazocine and EKC (ethylketocyclazocine)] and which is numbered “3” in the numbering system used for morphinans (e.g., morphine). When the 3-hydroxyl group is replaced by a number of small, polar, neutral residues, such as carboxamide and thiocarboxamide groups, the adjacent 4-position may be substituted with a hydroxyl to produce compounds with high affinity for the opioid receptor. (Wentland M: WO 2009023567; WO 2010011619; U.S. Pat. No. 6,784,187; U.S. Pat. No. 6,887,998; U.S. Pat. No. 7,262,298; U.S. Pat. No. 7,557,119). Compounds that bind to such receptors are likely to be useful in the treatment of diseases modulated by opiate receptors for example, mediating analgesia, combating drug and opioid addiction, alcohol addiction, drug overdose, mental illness, compulsive behavior, bladder dysfunctions, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, convulsions, lung edema, diarrhea, constipation, pruritus, cardiac disorders, cardioprotection, and cognitive, respiratory depression, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation, binge eating, anorexia, hyperalgesia, dyskinesia, anti-psychotic induced weight gain and as anti-tumor agents.
The potent antinociceptive actions of classical opioids such as morphine are traditionally considered to be predominantly mediated centrally through an action at the supraspinal or spinal level. Antinociceptive effects have also been demonstrated to result after local application of opioids in the periphery, for example, in mouse writhing, and in rat models of inflammation or neuropathic pain. These effects have been attributed to opioid induced actions mediated by peripheral opioid receptors. Neuroanatomical, molecular and electro-physiological studies have shown that such receptors are expressed on peripheral terminals of sensory neurons where they can modulate both afferent and efferent neuronal functions, resulting in antinociception. (Furst et al., J. Pharmacol Exp Ther. (2005) 312(2), 609-18). In addition, opioid receptors have been found on immune cells known to migrate into enteric tissues and the epithelial cells lining the gastrointestinal tract. As such, opioids interacting with peripheral opioid receptors without crossing the blood-brain barrier might be used as potent analgesics and are devoid of centrally mediated side effects are of interest in treating opioid mediated diseases.